Given concerns about the appropriate diagnosis for children with chronic, severe irritability, we defined severe mood dysregulation (SMD) to capture youth with severe irritability, as well as hyperarousal. SMD formed the basis for the new diagnosis of mood dysregulation disorder with dysphoria (DMDD)in DSM-5. Since the inception of this project (ZIA MH002786-17), approximately 450 highly irritable (i.e., those with SMD, DMDD, or sub-threshold DMDD) have enrolled into the project, along with more than 125 youth with ADHD. (Many DMDD patients have ADHD, and youth with ADHD tend to have less irritability than those with DMDD but more than healthy youth; hence they are an appropriate comparison group.) Approximately 50 new patients were recruited this year. Youth with DMDD suffer severe impairment, in terms of medications received, hospitalizations, and standardized measures of function. Irritability is one of the most common psychiatric symptoms in children, but there has been little brain-based research on it, and there are few evidence-based treatments. Recently, we published several major reviews and theoretical articles articulating a testable, heuristic, translational model of irritability to guide future research. The model posits that core deficits in pediatric irritability include aberrant responses to frustration and aberrant approach responses to threat. Aberrant responses to frustration implicate reward learning circuitry dysfunction e.g., deficits instrumental learning deficits that prevent adaptation to changing environmental contingencies, or exaggerated prediction error responses to the omission of an expected reward. In addition, evidence suggests that cognitive control deficits (specifically, deficient inhibitory control) may contribute to maladaptive behavior in response to either frustration or threat. Irritability is well-suited for the transdiagnostic, translational approach of the Research Domain Criteria (RDoC). We characterize irritability as a continuous variable, in DMDD and other groups, including youth with anxiety disorders or ADHD. We use frustrating tasks during neuroimaging, since a hallmark of irritability is difficulty tolerating frustration. Previously, we demonstrated behavioral and neural differences between irritable and non-irritable youth during a frustrating attentional task. We improved that paradigm and obtained fMRI data from approximately 200 youth with DMDD, ADHD, and/or anxiety disorders, as well as healthy youth. In a manuscript published this year, we found that irritability is associated with increased prefrontal and striatal engagement when youth attempt an attention orienting task after receiving frustrating feedback. This finding is more prominent in children than adolescents. Since prefrontal engagement is important in emotion regulation, this may indicate that prefrontal emotion regulation mechanisms are less efficient in irritable vs. non-irritable youth. Alternatively, in irritable youth, increased prefrontal engagement may be required after frustration to down-regulate exaggerated subcortical limbic responses e.g., in the striatum. These effects of irritability are present even when ADHD and anxiety are taken into account. In work published in 2018, we demonstrated associations between irritability and brain function when youth with DMDD, anxiety, or healthy subjects completed a threat-attention task. Because our translational model posits that both threat and reward (i.e., frustration) circuitry are implicated in irritability, we will next directly compare function in two brain circuits and the associations each have with irritability. Since youth with irritability have heterogeneous clinical presentations, precision medicine approaches would be fostered by testing whether irritable youth can be sub-grouped by dysfunction in threat vs. reward circuitry. We use previously acquired fMRI data from subjects who completed both the threat- and frustration-processing paradigms to develop and pilot new analytic methods and test these questions. We are also gathering data from a new, large sample of DMDD, anxious and ADHD subjects using the same two paradigms, to test these questions. In addition to the attention shifting frustration task described above, we have piloted two additional frustration tasks. The second frustration task differs from the first in the timing of frustration (short blocks of frustration, interspersed randomly with non-frustrating blocks, vs. a long block of non-frustration followed by a long bout of frustration) and in the cognitive task (attention orienting vs. cognitive flexibility). This second task allows us to test whether, across different task timing and cognitive tasks, increased irritability is associated with increased prefrontal engagement after frustration. We are now using new machine learning techniques to analyze data from 80 healthy youth or those with DMDD, anxiety, or ADHD. We have adapted the second task so that, while it maintains its unique methodological features, its design is sufficiently comparable to the frustrating attentional task to allow direct statistical comparisons. This will allow us to identify frustration-related findings that are robust to methodological variation, while also isolating the impact of different approaches on the findings. Such data will thus be informative not only about the brain mechanisms associated with irritability, but also future directions of research. In addition, both frustration tasks are accompanied by resting state data acquired pre- and post- the frustration task, so we can identify how frustration, elicited by two different techniques, impacts on intrinsic brain connectivity. Our third frustration task allows us to determine if irritability is associated with instrumental learning deficits at baseline and after frustration. Instrumental learning is the process by which people learn which of their behaviors will be rewarded. Deficits in such learning could lead to increased frustration in irritable youth. We successfully piloted this task outside the scanner and are now acquiring imaging data. A long-standing and important question in the literature is the extent to which deficits in cognitive control, particularly inhibitory control, play in the pathophysiology of temper outbursts. Given the significant overlap between ADHD symptoms and irritability, an important goal of this study is to differentiate the associations of each of these with deficient inhibitory ability. We are testing youth with DMDD, ADHD, and anxiety on an extensive battery of inhibitory control tasks. The use of this extensive battery allows us to derive latent variables which are more stable than those derived from an individual study and are thus more likely to yield replicable results. As noted above, a major focus of our work is treatment. We completed our double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of severe irritability. In a sample of 49 youth, we demonstrated that indeed, stimulant plus citalopram is more effective in reducing irritability than is stimulant plus placebo. These data have recently been published. Stimulant and SRI treatment tend to have fewer side-effects than atypical antipsychotic treatment, which is used frequently in youth with severe irritability. Therefore, this work has considerable public health importance. New treatment approaches are now being developed and tested under 15-M-0182 (NCT02531893); PI: Brotman.